HER2 mutation as an emerging target in advanced breast cancer.

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.

Bcl-2 dependent modulation of Hippo pathway in cancer cells.

INTRODUCTION: Bcl-2 and Bcl-xL are the most studied anti-apoptotic members of Bcl-2 family proteins. We previously characterized both of them, not only for their role in regulating apoptosis and resistance to therapy in cancer cells, but also for their non-canonical functions, mainly including promotion of cancer progression, metastatization, angiogenesis, and involvement in the crosstalk among cancer cells and components of the tumor microenvironment. Our goal was to identify transcriptional signature and novel cellular pathways specifically modulated by Bcl-2. METHODS: We performed RNAseq analysis of siRNA-mediated transient knockdown of Bcl-2 or Bcl-xL in human melanoma cells and gene ontology analysis to identify a specific Bcl-2 transcriptional signature. Expression of genes modulated by Bcl-2 and associated to Hippo pathway were validated in human melanoma, breast adenocarcinoma and non-small cell lung cancer cell lines by qRT-PCR. Western blotting analysis were performed to analyse protein expression of upstream regulators of YAP and in relation to different level of Bcl-2 protein. The effects of YAP silencing in Bcl-2 overexpressing cancer cells were evaluated in migration and cell viability assays in relation to different stiffness conditions. In vitro wound healing assays and co-cultures were used to evaluate cancer-specific Bcl-2 ability to activate fibroblasts. RESULTS: We demonstrated the Bcl-2-dependent modulation of Hippo Pathway in cancer cell lines from different tumor types by acting on upstream YAP regulators. YAP inhibition abolished the ability of Bcl-2 to increase tumor cell migration and proliferation on high stiffness condition of culture, to stimulate in vitro fibroblasts migration and to induce fibroblasts activation. CONCLUSIONS: We discovered that Bcl-2 regulates the Hippo pathway in different tumor types, promoting cell migration, adaptation to higher stiffness culture condition and fibroblast activation. Our data indicate that Bcl-2 inhibitors should be further investigated to counteract cancer-promoting mechanisms.

Breast and cervical cancer in transgender men: literature review and a case report.

Transgender individuals exhibit a higher prevalence of cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, coupled with suboptimal adherence to cancer screening recommendations, may lead to a higher incidence of cancers, such as breast and cervical cancer, and contribute to delayed diagnoses in transgender patients. Herein, we report a unique case of a transgender man with a history of alcohol and drug abuse, undergoing gender-affirming exogenous testosterone therapy, who developed synchronous locally advanced breast cancer and human papilloma virus (HPV)-related cervical cancer. He underwent concurrent chemoradiation for cervical cancer and surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, among them liver cirrhosis leading to an early death. Additionally, we have conducted a review of existing literature, including case reports, clinical studies, and review articles investigating the role of potential risk factors specifically related to breast and cervical tumors in transgender men. Gender-affirming testosterone therapy is common among transgender men to induce gender affirmation, but its link to breast cancer risk remains ambiguous, with studies being limited and sometimes contradictory. Conversely, HPV is a well-established cause of up to 99% of cervical cancers. Despite persistent risk for cervical cancer in transgender men who retain their cervix, several studies indicate notable disparities in screening adherence, due to personal and structural barriers. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may negatively influence the adherence to screening programs. Current cancer screening guidelines for this population are somewhat unclear, and specific programs based on more robust data are urgently required along with further tailored studies.

Breast and cervical cancer in transgender men: literature review and a case report Transgender individuals are persons whose gender identity does not conform to that typically associated with the sex to which they were assigned at birth. Transgender people may have more cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, along with suboptimal adherence to cancer screening, may lead to a higher incidence of cancers, among them breast and cervical cancer, and may also contribute to delayed diagnoses. Herein we report the case of a transgender man, recorded as female at birth but identifying as male, with a history of alcohol and drug abuse. He underwent testosterone therapy in order to affirm his gender. Moreover, he refused cancer screening, due to personal and social barriers. During the transition, he developed simultaneously a locally advanced breast cancer and a cervical cancer, the latter related to an infection from Human Papillomavirus. The patient was treated with chemoradiation for cervical cancer, and with surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, partly related to his previous lifestyle. Additionally, we have conducted a review of existing literature on the topic. Trangender men usually undergo testosterone to induce gender-affirmation. The role of testosterone therapy in breast cancer development remains unclear, with studies being contradictory. Conversely, Human Papillomavirus is a well-established cause of cervical cancers. Transgender men who retain their cervix are at risk for cervical cancer. Despite the persistent risk, notable disparities in screening adherence, due to personal and structural barriers, are reported. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may contrtibute to the low adherence to screening programs. Furthermore, screening guidelines are somewhat unclear, and specific programs are urgently required.

DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study.

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.

Reconstruçäo mamária imediata e critérios oncológicos: nossas atuais orientaçoës / Immediated breast reconstruction and oncologic criteria: our current definition

Os autores, através de uma revisäo da literatura, propöem-se a verificar os parâmetros oncológicos para a definiçäo dos casos "candidatáveis" a yna reconstruçäo imediata após mastectomia de Patey. Em relaçäo ao problema das recidivas locais, pelos resultados observados, evidencia-se que a hipótese de uma prótese sob o músculo grande peitoral mascarar essas recidivas näo é estatisticamente quantificável. A reconstrçäo näo interfere também com o carcinoma mamário, seja em termos de sobrevida ou de intervalo livre da doença. Consideramos que o tempo médio de aparecimento da recidiva, também nos casos N+, é de cerca de dois anos; achamos que estas pacientes com linfonodos positivos, se motivadas e candidatas a uma mastectomia modificada, näo devem ser excluídas de um programa reconstrutivo imediato. A baixa morbidade, os custos limitados, as vantagens psicológicas e o rápido início das terapias complementares fazem da reconstruçäo imediata um recurso fundamental. Conseqüentemente, há uma melhora da qualidade de vida também para os casos com limitadas perspectivas de sobrevida